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| United States Patent |
5,223,614
|
|
Schromm
, et al.
|
June 29, 1993
|
New quaternary ammonium compounds, their preparation and use
Abstract
Compounds of formula
##STR1##
wherein the substituents are defined hereinbelow, useful in the treatment
of bronchospasm are described.
| Inventors:
|
Schromm; Kurt (Ingleheim am Rhein, DE);
Mentrup; Anton (Wiesbaden, DE);
Renth; Ernst-Otto (Ingleheim am Rhein, DE);
Mualcevic; Gojko (Ingleheim am Rhein, DE);
Traunecker; Werner (Munster-Sarmsheim, DE)
|
| Assignee:
|
Boehringer Ingelheim GmbH (Ingleheim am Rhein, DE)
|
| Appl. No.:
|
603585 |
| Filed:
|
October 25, 1990 |
Foreign Application Priority Data
| Current U.S. Class: |
544/105; 546/184; 546/221; 548/215; 548/221; 564/281; 564/282; 564/291; 568/705 |
| Intern'l Class: |
C07D 265/36 |
| Field of Search: |
564/283,281,282,291
544/105
546/184,221
548/215,221
574/230.5,299,330,375
568/705
|
References Cited
U.S. Patent Documents
| 4599335 | Jul., 1986 | Rentzea et al. | 564/282.
|
Other References
Chemcial Abstracts, vol. 101, p. 772, 191939z, 1984.
Chemical Abstracts, vol. 80, p. 274, No. 7, 36875e, 1974.
|
Primary Examiner: Dees; Jose G.
Assistant Examiner: Carr; Deborah D.
Attorney, Agent or Firm: Frankhouser; D. E., Stempel; A. R., Timbers; M-E. M.
Parent Case Text
This is a continuation, of application Ser. No. 286,442, filed Dec. 19,
1988, now abandoned.
Claims
What is claimed is:
1. A compound of formula
wherein
n is an integer 1, 2, 3, 4 or 5;
R.sub.1 is H, CH.sub.3, OCH.sub.3, Cl or F;
R.sub.2 is H, R.sub.3 O, CH.sub.2 OH, NHCHO, NHCOCH.sub.3, NHSO.sub.2
CH.sub.3, or NHCONH.sub.2 ;
R.sub.3 is H, acyl, N,N-dialkylcarbamoyl, the group R.sub.3 O being in the
4 or 5 position; or the group
##STR64##
wherein R.sub.3 is as defined above and R.sub.8 is H or CH.sub.3 ;
R.sub.4 is H, CH.sub.3, or C.sub.2 H.sub.5 ;
R.sub.5 is H or CH.sub.3 ;
R.sub.6 is H or CH.sub.3 ;
R.sub.7 is a single bond or a divalent bridging member which may also be
bound to the ammonium nitrogen via ring atoms of a heterocyclic group;
R.sub.8 is H, or --CH.sub.3 ;
##STR65##
is a quaternary ammonium group, An.sup.- is 1 equivalent of an anion, a
pure enantiomer thereof, or a mixture of enantiomers, or a salt with
inorganic or organic acids.
2. The compounds as recited in claim 1, wherein the group
##STR66##
wherein n and R.sub.1 to R.sub.6 are as recited in claim 2 and m is an
integer 2, 3, 4, 5 or 6;
A is a single bond or NH--CO--(C.sub.1-4)-alkylene;
B is a single bond, --O--(C.sub.1-4)-alkylene, --(C.sub.1-4)-alkylene, or
--NH--CO--(C.sub.1-4)-alkylene;
D is --(C.sub.1-4)-alkylene
E is
##STR67##
wherein R9 is (C.sub.1-4)-alkyl;
R10 is (C.sub.1-4)-alkyl;
R11 is (C.sub.1-4)-alkyl,
(C.sub.1-4)-alkylene-COO--(C.sub.1-4)-alkylene-SO.sub.3 --,
(C.sub.1-4)-alkylene-OH, (C.sub.1-4)-cycloalkyl, R.sub.9 and R.sub.10
together are (C.sub.4-6)-alkylene.
Ar is arylene, and
##STR68##
is N-heterocycles which may be condensed with a benzene ring and may be
substituted or unsubstituted and may optionally contain one or more
additional heteroatoms in the ring.
3. The compound as recited in claim 2 wherein Ar is unsubstituted or
substituted phenylene or naphthylene.
4. A pharmaceutical composition of matter useful in the treatment of
bronchospasm comprising a therapeutically effective amount of a compound
as recited in claim 2 and a pharmaceutically acceptable carrier.
5. A method of treating bronchospasm in a warm-blooded animal comprising
administering to said animal a therapeutically effective amount of a
compound as recited in claim 1.
Description
The invention relates to quaternary ammonium compounds, and the preparation
and use thereof. The compounds of the invention may be prepared by methods
known per se and used as pharmaceuticals, particularly for inhalation.
We have found that the introduction of a quaternary ammonium group at a
suitable point in the molecules of known broncholytically active compounds
which are effective when inhaled makes it possible to eliminate unwanted
systemic side effects to a great extent whilst substantially retaining the
broncholytic (topical) effect. We have found that the nature of the
quaternary ammonium grouping may be selected from a wide range of
variations without crucially affecting the differentiation between
desirable and undesirable effects according to the invention.
According to the invention, we provide compounds of formula I
##STR2##
wherein Q represents a substituted phenyl group;
R represents a group, such as an alkoxy, arylalkoxy, aryloxyalkoxy, aryl,
aryloxy arylcarbonamido group, a heterocyclic group or a heterocyclically
substituted carbonamido group, which includes also a quaternary ammonium
grouping;
R.sub.4 represents H, CH.sub.3 or C.sub.2 H.sub.5 ;
R.sub.5 represents H or CH.sub.3 ;
R.sub.6 represents H or CH.sub.3 ;
n represents an integer selected from 1, 2, 3, 4 and 5.
The compounds of the invention may in one preferred embodiment be
represented essentially by the formula Ia
##STR3##
in which, unless otherwise stated, n represents an integer selected from
1, 2, 3, 4 and 5;
R.sub.1 represents H, CH.sub.3, OCH.sub.3, Cl, or F;
R.sub.2 represents H, R.sub.3 O--, --CH.sub.2 OH, --NHCHO, --NHCOCH.sub.3,
--NHSO.sub.2 CH.sub.3, or --NHCONH.sub.2 ;
R.sub.3 represents H, acyl, or N,N-dialkylcarbamoyl, the groups R.sub.3 O
being in the 4- or 5- positions;
the group II
##STR4##
may also represent one of the groups
##STR5##
wherein R.sub.3 is as hereinbefore defined and R.sub.8 represents H or
CH.sub.3 ;
R.sub.4 represents H, CH.sub.3, or C.sub.2 H.sub.5 ;
R.sub.5 represents H or CH.sub.3 ;
R.sub.6 represents H or CH.sub.3 ;
R.sub.7 represents a single bond or a divalent bridging member which may
also be bound to the ammonium nitrogen via ring atoms of a heterocyclic
group;
##STR6##
represents a quaternary ammonium group; An.sup..crclbar. represents an
anion.
In a further preferred embodiment, the grouping
##STR7##
primarily represents one of the groups
##STR8##
n and R.sub.1 to R.sub.6 being as defined hereinbefore.
In the above definitions of (IIIa) to (IIIi),
m represents an integer selected from 2, 3, 4, 5 and 6;
##STR9##
represents a nitrogen heterocycle which may be condensed with a benzene
ring and which may be substituted or unsubstituted and may optionally
contain one or more additional heteroatoms in the ring;
Ar represents arylene, preferably unsubstituted or substituted phenylene or
naphthylene;
A represents a single bond or a NH--CO--(C.sub.1-4)-alkylene group;
B represents a single bond or an --O--(C.sub.1-4)-alkylene,
--NH--CO--(C.sub.1-4)-alkylene, or --(C.sub.1-4)-alkylene group;
D represents a --(C.sub.1-4)-alkylene group; and
E represents one of the groups
##STR10##
(in which R.sub.9 represents a (C.sub.1-4)-alkyl group;
R.sub.10 represents a (C.sub.1-4)-alkyl group; or
R.sub.9 and R.sub.10 together represent a (C.sub. 4-6)-alkylene group; and
R.sub.11 represents a (C.sub.1-4)-alkyl,
(C.sub.1-4)-alkylene-COO.sup..crclbar.,
(C.sub.1-4)-alkylene-SO.sub.3.sup..crclbar., (C.sub.1-4)-alkylene-OH, or
(C.sub.3-6)-cycloalkyl group; and the group
##STR11##
is as defined above).
Typical examples of E include
--N.sup..sym. (CH.sub.3).sub.3,
--N.sup..sym. (CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH.sub.2
SO.sub.3.sup..crclbar.,
--N.sup..sym. (CH.sub.3).sub.2 --(CH.sub.2).sub.4 --SO.sub.3.sup..crclbar.,
--N.sup..sym. (CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CO.sub.2.sup..crclbar.,
##STR12##
Particular mention should be made of the following preferred definitions
for the grouping
##STR13##
in which the groupings and groups are as defined above:
##STR14##
The alkyl and alkylene groups in the above definitions may be
straight-chained or branched. Unless otherwise stated, they contain 1 to
6, preferably 1 to 4, and most particularly 1 or 2 carbon atoms. This also
applies to the carbon chains which are components of other groups.
Examples of substituents in aryl(ene) include, in particular, F, Cl,
CH.sub.3 and CH.sub.3 O groups. The terms "aryl" and "arylene" refer to
the appropriate groups derived from benzene or naphthalene. "Acyl groups"
in this case denote carboxylic acid groups with up to 7 carbon atoms,
particularly acetyl. The bridge R.sub.7 may be linked to the nitrogen atom
of the quaternary ammonium group. Alternatively, if the quaternary
ammonium group is part of a heterocyclic group, the bridge may be
connected to another ring atom of the heterocyclic group. Groups falling
into this latter category include in particular
##STR15##
(in which R.sup.11 represents H or C.sub.1-4 -alkyl), and triazines.
In a further preferred embodiment of the invention
R.sub.1 represents H, CH.sub.3, OCH.sub.3, Cl or F;
R.sub.2 represents OH or, when R.sub.1 equals Cl or F, R.sub.2 may also
represent H; or
R.sub.1 and R.sub.2 together may also represent
##STR16##
(in which R.sub.8 is as hereinbefore defined) R.sub.3 represents a
hydrogen atom;
R.sub.4 represents H or C.sub.2 H.sub.5 ;
R.sub.5 and R.sub.6 both represent H or both represent CH.sub.3 ;
n represents an integer selected from 1, 2 and 3;
R.sub.7
##STR17##
represents a group
##STR18##
whilst B, D and R.sub.11 are as hereinbefore defined).
Particular mention should be made of the compounds in which the following
combinations of substituents occur:
(a) R.sub.1 represents a methyl or methoxy group, R.sub.2 represents a
hydroxyl group, and R.sub.3 represents a 4-hydroxyl group;
(b) R.sub.1 represents a hydrogen atom, R.sub.2 represents a hydroxyl
group, and R.sub.3 represents a 4- or 5-hydroxyl group;
(c) R.sub.1 and R.sub.2 together represent
##STR19##
R.sub.3 represents a 4- or 5-hydroxyl group; R.sub.4 represents a hydrogen
atom, if R.sub.5 and R.sub.6 represent methyl groups, but C.sub.2 H.sub.5,
if R.sub.5 and R.sub.6 represent H;
##STR20##
represents
##STR21##
(in which R.sub.12 and R.sub.13 represent CH.sub.3, CH.sub.2
--COO.sup..crclbar., CH.sub.2 --CH.sub.2 --COO.sup..crclbar. or CH.sub.2
--CH.sub.2 --CH.sub.2 --SO.sub.3.sup..crclbar.).
The compounds according to the invention may occur as mixtures of
enantiomers, particularly as racemates, and optionally either as pairs of
diastereoisomers or as pure enantiomers, and as salts with (preferably
physiologically acceptable) acids, and the invention extends to all such
forms of the compounds of formula I.
The compounds of the invention may be prepared by a variety of methods.
Accordingly, in a further aspect of the invention, we provide a process for
preparing compounds of formula I as described above, wherein
a) a compound of formula IV
##STR22##
wherein n, Q, R.sub.4, R.sub.5 and R.sub.6 are as defined above, R' is a
tertiary amino group which corresponds at least in part to the quaternary
ammonium group-containing group R, or a protected form thereof in which
any hydroxyl group or amino group it is desired to protect is protected by
hydrogenolytically-removable protecting groups, is reacted with an
alkylating agent, and any protecting groups present are removed by
hydrogenolysis;
or
b) if it is desired to prepare a compound of formula VII
##STR23##
wherein n, R.sub.4, R.sub.5, R.sub.6 and Q are as defined above and
R.sub.7 ' represents a group R.sub.7 which is bound to the quaternary
ammonium nitrogen via an aliphatic carbon atom,
a compound of formula VIII
##STR24##
(wherein the symbols are all defined as above and X represents a leaving
group is reacted with a tertiary amine
##STR25##
to provide the desired quaternary ammonium compound, followed, if desired,
by separation of any mixture of enantiomers into pure enantiomeric forms
or other enantiomeric mixtures, and formation of any desired acid addition
salts.
Process (a) above is suitable for preparing compounds of formula I in which
the quaternary ammonium group is not in the form
##STR26##
Compounds selected from Cl--(C.sub.1-4)-alkylene-SO.sub.3 Na and
HO--(C.sub.1-4)-alkylene-SO.sub.2 --O--(C.sub.1-4)-alkylene-SO.sub.3 Na
are particularly suitable for the introduction of a
(C.sub.1-4)-alkylene-SO.sub.3.sup..crclbar. group.
The reaction is expediently carried out in an inert polar solvent at
ambient temperature or at an elevated temperature up to about 100.degree.
C.
The starting materials of formula IV may be obtained by methods known per
se. Thus, aminoketones of formula V
##STR27##
wherein Q, R.sup.4, R.sup.5, R.sup.6, R.sup.1 and n are as defined above,
or Schiff base of the formula VI
##STR28##
(wherein the symbols are defined as hereinbefore) may be converted into
compounds of formula IV by reduction with hydrogen in the presence of
hydrogenation catalysts such as palladium, platinum or Raney nickel, or by
reaction with hydrides such as sodium hydride in suitable solvents such as
ethanol. Any protecting groups present may if necessary or desired be
removed in the usual way.
In process (b) above, the leaving group X is preferably a chlorine, bromine
or iodine atom or an alkyl- or arylsulphonic acid group.
The reaction is preferably effected in a protic or aprotic solvent such as
methanol or dimethylformamide at temperatures of between ambient
temperature and about 100.degree. C.
Any hydrogenolytically-cleavable protecting groups present may be removed
after the reaction if necessary or desired by conventional methods.
The starting compounds of formula VIII may be prepared, for example, from
aminoketones of formula IX
##STR29##
by reaction thereof with a hydride such as sodium hydride or diborane.
The compounds of formula IX may in turn be obtained by methods known per
se.
Any protecting groups present which it is desired to remove may expediently
be removed by hydrogenolysis with palladium as catalyst in an inert
solvent.
The compounds according to the invention always will contain at least one
asymmetric carbon atom. In order to obtain compounds of formula I in the
form of specific enantiomers or (in the case of several centres of
asymmetry) diastereoisomeric pairs of antipodes, it is convenient to use
starting materials, e.g. of formula IV or X, in which the desired
configuration is already present at the centres of asymmetry in question.
The compounds according to the invention may if desired by converted in a
manner known per se into salts. For pharmaceutical use these will
preferably be formed with physiologically acceptable acids, and these may
be either organic or inorganic.
Suitable acids for salt formation include, for example, inorganic acids
such as hydrochloric, hydrobromic, sulphuric and phosphoric acids, and
organic acids such as methylsulphuric, tartaric, fumaric, citric, maleic,
succunic, gluconic, malic, p-toluenesulphonic, methanesulphonic and
amidosulphonic acids.
The compounds of the invention are suitable for use in pharmaceutical
compositions. In particular they have broncholytic, spasmolytic and
anti-allergic activity, they increase ciliary activity and reduce
inflammatory/ exudative reactions. They may therefore be used inter alia
for treating all types of asthma and bronchitis.
The dosage for therapeutic and prophylactic use will in general depend on
the nature and gravity of the illness in question.
For adults, the dosage for the preferred route of administration, namely
inhalation, is preferably from 0.001 to 0.5 mg per day. The preparations
are obtained in conventional manner using normal diluents, excipients
and/or carriers. The compounds according to the invention may also be
combined with other active substances, e.g. parasympatholytics (e.g.
ipratropium bromide, oxytropium bromide), secretolytics (e.g. bromhexine,
ambroxol), antibiotics (e.g. doxycycline), corticosteroids (e.g.
beclomethasone dipropionate, flunisolide, budesonide) or other anti-asthma
preparations such as disodium cromoglycate, nedocromil and anti-allergic
substances.
The following non-limiting examples illustrate formulations which
incorporate the compounds of the invention:
1. Powder for inhalation
Micronised powdered active substance (compound of formula I; particle size
about 0.5 to 7 microns) is packed into hard gelatine capsules in
quantities of 0.02 mg with 10 mg of micronised lactose and, optionally,
suitable quantities of other active substances. The powder is inhaled from
conventional inhaling devices, e.g. according to DE-A-3345722.
2. Metering aerosol
______________________________________
Active substance according
0.1% by weight
to Example 8 hereinbelow
Sorbitane trioleate 0.5% by weight
Monofluorotrichloromethane and
difluorodichloromethane (2:3)
99.4% by weight
______________________________________
The mixture is packed into metering aerosols of suitable type. The metering
device is designed, for example, so as to release 0.05 ml of the
preparation on each actuation.
The advantage of the compounds according to the invention is that, when
they are inhaled, by comparison with known bronchospasmolytic
.beta.-mimetics, they show a particularly marked selectivity in the
relationship between bronchospasmolysis and increased heart rate, positive
inotropic effects and tremor. The broncholytic activity is achieved with
low doses and the activity is long-lasting.
Some pharmacological activity data for compounds according to the invention
are given hereinafter.
The EC.sub.50 by inhalation was determined on conscious, fasting
guinea-pigs according to Kallos P. and Pagel, W. (Acta med. scand. 91, 292
(1937)) (histamine spasm). The substances were tested in the form of an
aqueous solution.
______________________________________
EC.sub.50
%
______________________________________
A 0.06
B 0.06
C 0.09
D 0.06
E 0.5
F 0.3
G 0.02
H 0.05
I 0.02
J 0.004
K 0.02
______________________________________
__________________________________________________________________________
Compounds tested
##STR30##
Compound Q
##STR31##
__________________________________________________________________________
A:
##STR32##
N.sup..sym. (CH.sub.3).sub.3 Cl.sup..crclbar.
B:
##STR33##
##STR34##
C:
##STR35##
N.sup..sym. (CH.sub.3).sub.3 Cl.sup..crclbar.
D:
##STR36##
.sup..sym. N(CH.sub.3).sub.3 Cl.sup..crclbar.
E:
##STR37##
.sup..sym. N(CH.sub.3).sub.3 Cl.sup..crclbar.
__________________________________________________________________________
1
Compounds of formula
##STR38##
Compound
G
__________________________________________________________________________
F:
##STR39##
G:
##STR40##
H:
##STR41##
I:
##STR42##
J:
##STR43##
K:
##STR44##
__________________________________________________________________________
The following non-limiting examples illustrate processes whereby the
compounds of the invention may be synthesised.
EXAMPLE 1
##STR45##
1.9 g of
5'-hydroxy-8'-[1-hydroxy-2-[4-(4-pyridyl)-2-methyl-2-butylamino]-ethyl]-2H
-1,4-benzoxazin-3-(4H)-one-monohydrochloride are dissolved in a mixture of
3 ml of dimethylformamide and 1 ml of water and 1.27 g of methyliodide are
added. After 12 hours the solution is mixed with 5 ml of alcohol,
acidified with conc. HCl and diluted with acetone; the crystals
precipitated are suction filtered after about 1 hour and 1.2 g of the
compound are obtained by precipitation with water, conc. hydrochloric acid
and alcohol.
M.p. 207.degree.-209.degree. C. 56% of theory.
The starting compound may be prepared by the following method:
##STR46##
EXAMPLE 2
##STR47##
3.7 g of
5'-benzyloxy-8'-[1-hydroxy-2-[3-(4-dimethylaminophenyl)-2-methyl-2-propyla
mino]-ethyl]-2H-1,4-benzoxazin-3-(4H)-one-monohydrochloride are combined
with 2.1 g of methyliodide in 7.4 ml of DMF and reacted for 12 hours.
After dilution of the solution with acetone the ammonium iodide
hydrochloride is obtained which is converted into the ammonium
chlorohydrochloride compound (m.p. 195.degree.-197.degree. C.) by
conversion with hydrochloric acid or by means of the ammonium hydroxide
compound and treating with hydrochloric acid.
3.7 g of this benzyloxy compound are debenzylated in 50 ml of methanol
using palladium/charcoal as catalyst under normal conditions and 2 g of
the title compound are obtained. M.p. 187.degree. C. (decomp.); (6.28% of
theory).
The starting compound may be prepared by the following method:
##STR48##
EXAMPLE 3
##STR49##
3.2 g of
5'-benzyloxy-8'-[1-hydroxy-2-[3-(4-dimethylamino-ethoxyphenyl)-2-methyl-2-
propylamino]-ethyl]-2H-1,4-benzoxazin-2-(4H)-one-monohydrochloride are
combined with 0.41 g of .beta.-propiolactone in 6 ml of acetone and left
to react for 12 hours at ambient temperature. After dilution with acetone,
the crystals precipitated are suction filtered and 2.4 g of the compound
are obtained (Mp. 123.degree.-126.degree. C.).
2.3 g of the benzyloxy compound are debenzylated in 50 ml of methanol with
the addition of palladium charcoal and 1.7 g of the title compound are
obtained. (Mp. 173.degree.-175.degree. C., 94% of theory).
The starting compound may be prepared by the following method:
##STR50##
The following compounds may be synthesised analogously to the Examples
given:
##STR51##
EXAMPLE 4
##STR52##
4.4 g of
5'-hydroxy-8'-[1-hydroxy-2-[3-(4-chloroacetaminophenyl)-2-methyl-2-propyla
mino]-ethyl]-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride, 6 ml of pyridine
and 25 ml of methanol are refluxed for 6 hours, then after the methanol
and pyridine have been distilled off the oily residue is dissolved in
alcohol and 3.8 g of the title compound are obtained.
(Mp. 190.degree.-192.degree. C.; 77.5% of theory).
The starting compound may be prepared by the following processes:
##STR53##
EXAMPLE 5
##STR54##
2.7 g of
6'-hydroxy-8'-[1-hydroxy-2-[3-(4-chloracetaminophenyl)-2-methyl-2-propylam
ino]-ethyl]-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride, 25 ml of methanol
and 3 ml of 30% trimethylamine solution are stirred for 12 hours at
ambient temperature, concentrated and the oil obtained is dissolved in
alcohol. After 1 hour the crystals precipitated are suction filtered and 2
g of the title compound are obtained. (Mp. 203.degree.-206.degree. C., 65%
of theory)
The starting compound may be prepared by the following process:
##STR55##
The following compounds are prepared analogously:
##STR56##
EXAMPLE 6
##STR57##
4.2 g of dibenzyloxy compound (see below) are debenzylated with hydrogen in
methanol with palladium charcoal as catalyst under normal conditions and
2.5 g of the title compound are obtained. (81% of theory).
The starting compound may be prepared by the following method:
##STR58##
EXAMPLE 7
##STR59##
3.5 g of benzoyloxy compound (see below) are debenzylated with hydrogen in
50 ml of methanol with the addition of 0.5 g of 5% palladium charcoal as
catalyst under normal conditions. After the uptake has ceased the catalyst
is removed by suction filtering, the methanol is distilled off under
reduced pressure using a Rotavapor and the residue is dissolved in
approximately 90% alcohol. After seeding the crystals precipitated are
suction filtered, washed with alcohol and dried. 2.9 g of the title
compound are obtained, (Mp. 240.degree. C.; 93% of theory).
The starting compound may be prepared by the following process (Bz equals
benzyl)
##STR60##
EXAMPLE 8
##STR61##
2.4 g of benzyloxy compound are debenzylated with hydrogen in 50 ml of
methanol and 10 ml of water with the addition of 0.5 g of
palladium/charcoal as catalyst under normal conditions. After the uptake
has ceased the catalyst is removed by suction filtering, the methanol is
distilled off under reduced pressure using a Rotavapor and the residue is
triturated with alcohol. The crystals precipitated are suction filtered
and reprecipitated once with water/alcohol. 1.6 g of the title compound
are obtained, (mp. 175.degree. C., decomp., 71% of theory)
The starting compounds may be obtained by the following process:
##STR62##
The following compounds may be synthesised analogously to the Examples:
##STR63##
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